A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives 1a-2c) in order to test the compounds' ability to inhibit both cancer cell growth and topoisomerase I and II activity. The ability of human topoisomerase I (hTOPI) and II to relax supercoiled plasmid DNA in the presence of various concentrations of the tacrine-coumarin hybrid molecules was studied with agarose gel electrophoresis. The biological activities of the derivatives were studied using MTT assays, clonogenic assays, cell cycle analysis and quantification of cell number and viability. The content and localization of the derivatives in the cells were analysed using flow cytometry and confocal microscopy. All of the studied compounds were found to have inhibited topoisomerase I activity completely. The effect of the tacrine-coumarin hybrid compounds on cancer cells is likely to be dependent on the length of the chain between the tacrine and coumarin moieties (1c, 1d = tacrine-(CH2)8-9-coumarin). The most active of the tested compounds, derivatives 1c and 1d, both display longer chains.

• Keywords
• A549, DNA, cytotoxicity, lung carcinoma cells, tacrine-coumarin derivatives, topoisomerases I, II,
• MeSH
• A549 Cells MeSH
• DNA Topoisomerases, Type I metabolism   MeSH
• DNA Topoisomerases, Type II metabolism   MeSH
• Topoisomerase I Inhibitors chemistry   pharmacology   MeSH
• Topoisomerase II Inhibitors chemistry   pharmacology   MeSH
• Coumarins chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Tumor Cells, Cultured MeSH
• Cell Proliferation drug effects   MeSH
• Poly-ADP-Ribose Binding Proteins antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Tacrine chemistry   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA Topoisomerases, Type I MeSH
• DNA Topoisomerases, Type II MeSH
• Topoisomerase I Inhibitors MeSH
• Topoisomerase II Inhibitors MeSH
• Coumarins MeSH
• Poly-ADP-Ribose Binding Proteins MeSH
• Antineoplastic Agents MeSH
• Tacrine MeSH
• TOP1 protein, human MeSH Browser
• TOP2A protein, human MeSH Browser

A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12-17 and urea heterodimers 18-22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14-17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.

• Keywords
• 7-MEOTA-tacrine heterodimers, HL-60, calf thymus DNA, human dermal fibroblasts, topoisomerases,
• MeSH
• Acridines chemical synthesis   chemistry   pharmacology   MeSH
• A549 Cells MeSH
• Fibroblasts drug effects   MeSH
• HL-60 Cells MeSH
• Humans MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents chemical synthesis   chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Tacrine chemistry   pharmacology   MeSH
• Thiourea chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-methoxy-1,2,3,4-tetrahydroacridin-9-amine MeSH Browser
• Acridines MeSH
• Antineoplastic Agents MeSH
• Tacrine MeSH
• Thiourea MeSH